The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies indicate that: (1) While it is possible to differentiate D1 dopamine agonists in vitro on the basis of their efficacy in stimulating adenylyl cyclase, differences in efficacy have not been correlated with any other pharmacological effect of these drugs. Other biochemical indications of efficacy are being assessed for their relation to efficacy in producing behavioral effects (2) Many of the known dopamine D2 agonists also have affinity for dopamine D3 receptors. Studies are being conducted in order to discover drugs that are selective for both D2 and D3 receptors. Subsequent studies will characterize the pharmacology of these selective compounds in order to learn more about the functional roles of these receptor subtypes. (3) The pharmacology of dopamine D2 agonists is being characterized in a cell line that expresses a D2 receptor that is functionally similar to brain dopamine D2 receptors. Because these D2 receptors are expressed in the absence of other dopamine receptor subtypes, this cell line is a model system for studying the function and regulation of the D2 receptor. The findings from these studies suggest that the dopamine D2 receptor regulates cyclase inhibition predominantly via the Gi1 and/or Gi2 subunits of G alpha. Using this system the intrinsic efficacies of dopamine D2 agonists have been characterized, and results will be of importance for differentiating the functional/behavioral consquences of agonist actions at D2 and D3 receptors. (6) The pharmacology of D3 dopamine receptor agonists, PD 128,907 and 7 OH DPAT, is being characterized. The behavioral studies have indicated that D3 agonists are not efficacious behavioral stimulants. (7) Because there are only limited selective ligands for the dopamine D3 receptor, we are preparing novel compounds that are designed to be selective at this dopamine receptor subtype.